At a Glance

Familial defective apolipoprotein B-100 (FDB) is a phenocopy of familial hypercholesterolemia (FH) and a significant cause of coronary heart disease (CHD). This fairly common cause of FH is an autosomal dominant disorder caused by mutations in the ligand-binding domain (exon 26) of the APOB gene on chromosome 2p24.1 that result in defective binding of low-density lipoprotein particles (LDL-P) to the intact LDL receptor (LDLR). There are two protein products from the APOB gene: ApoB-100 (the ApoB of VLDL and LDL; 4,536 amino acids long); and ApoB-48 (the ApoB of chylomicrons; 2,152 amino acids long).

In FDB, mutations in APOB cause defective binding of ApoB-100 with LDLR, leading to impairments in LDL catabolism and decreased clearance of circulating LDL-P. The clinical manifestations are similar to those of diseases caused by mutations of the LDLR, such as FH (i.e. elevated levels of total cholesterol and LDL-C, the occurrence of tendon xanthomas and premature CHD).

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Although the FDB heterozygous phenotype is generally less severe than that of classical heterozygous LDLR-defective FH, differentiating heterozygous FH from FDB can be difficult by clinical criteria alone. Individuals doubly heterozygous for an LDLR mutation (heterozygous FH) plus an APOB mutation (FDB) usually have plasma LDL-C levels intermediate between that of FH heterozygotes and FH homozygotes but can have plasma LDL-C levels as high as that seen in FH homozygotes. FDB subjects tend to have triglyceride and high-density lipoprotein cholesterol (HDL-C) levels within the normal range.

In FDB heterozygotes, LDL-C levels vary between approximately 100 and 400 mg/dL, with a mean about 280 mg/dL.

The most definitive way to confirm the FDB diagnosis is direct molecular detection of the genetic mutation in APOB gene. The most common FDB genetic defect is the missense mutation R3500Q in ApoB-100, which has a frequency of 1:500-600 individuals in populations of European descent. This mutation is generally associated with less coronary arteriosclerosis than heterozygous FH (reflecting quantitative differences in plasma LDL-C levels). Another mutation, R3500W, also exists and is rare in individuals of European origin but more common among Chinese populations. A third, rarer APOB ligand domain mutation causing FDB, R3531C, also impairs binding of LDL to the LDLR and contributes to LDL-C elevation, albeit milder than that associated with R3500Q or classic FH.

Results Indicative of the Disorder

For clinical criteria, see the chapter on Familial Hypercholesterolemia, as the clinical manifestations of FH and FDB are nearly identical.

Presence of one of the following APOB gene mutations is also indicative of the disorder: R3500Q, R3500W or R3531C. The R3500Q mutation is the major determinant of LDL-C levels and coronary artery calcification in the old order Amish community in Pennsylvania owing to a founder effect. It is possible that mutations in other ApoB domains may alter ligand properties if none are found in the putative ligand binding domain.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Some medications or other conditions that might affect the diagnosis of the disorder using laboratory tests include:

LDL cholesterol concentration should not be used to assess FDB if any of the previous drugs are being taken. In such cases, a diagnosis can be made using genetic testing for the mutations mentioned. Note that a negative result for the most frequent mutations does not completely rule out the presence of FDB.

What Lab Results Are Absolutely Confirmatory?

FDB needs distinguished from classical FH, familial combined hyperlipidemia (FCH) and polygenic hypercholesterolemia. The distinction between FDB and FH cannot be made by LDL-C concentration alone. FDB subjects do not usually have relatives with lipoprotein abnormalities of multiple types, which is characteristic of FCH, but the presence of other lipoprotein abnormalities does not rule out the diagnosis of FDB.

Confirmation of the FDB diagnosis requires either a demonstration of decreased ApoB-LDLR binding or the detection of the causative genetic mutation in APOB segregating within the family, in combination with elevated plasma LDL-C levels and perhaps premature atherosclerosis and/or the presence of xanthomata.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Fasting (10-14 hours) measurement of LDL-C, HDL-C and TG and follow-up of these biomarkers confirms the clinical Dx.

Genetic mutation screening of the APOB gene ligand binding domain using DNA extracted from white blood cells (WBCs) and polymerase chain reaction (PCR)-based techniques are also confirmatory. If no mutation is found, screen for FH mutations in the LDLR and PCSK9 genes.

The affected allele can also be detected by hybridization with allele-specific oligonucleotides, by single-strand mobility shift assays and by direct measurement of receptor binding of LDL.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Lipoprotein X (LpX), if present, is measured as LDL-C and could lead to a false diagnosis of FH. LpX is a lipoprotein that accumulates in cholestatic liver disease. LpX cholesterol concentration can be elevated to levels consistent with heterozygous and homozygous FDB and even higher. LDL-C, if determined using the Friedewald equation, should be measured when the patient has fasted for 10-14 hours. The presence of chylomicrons and marked hypertriglyceridemia could lead to the underestimation of LDL-C. Lipoprotein testing to diagnose FDB should not be performed when the patient is taking LDL lowering drugs, such as statins or niacin. Genotyping assays can be successfully performed in this setting.